Abstract. During the first three years of this award, we have characterized mouse models of lung adenocarcinoma initiated by doxycycline-inducible transgenes encoding the two common forms of mutant EGFR found in the corresponding type of human cancer. These mice develop tumors indistinguishable from the human cancers; the tumors regress when the oncogene is de-induced or when the mutant kinase is inhibited with drugs used in patients, and they develop drug resistance under certain conditions, in some cases as a result of a secondary mutation in EGFR also found in about half of drug-resistant tumors in patients. We now propose to extend our work with these mouse models in several ways with the goals of (i) evaluating genes and proteins (including tumor suppressor genes, members of the EGFR family, and phosphotyrosine-containing proteins) that might influence EGFR-initiated lung tumorigenesis; (ii) discovering additional genes that contribute to tumor formation, progression or drug resistance; (iii) assessing the potential of tumors with various genotypes to metastasize and become established cell lines in culture; and (iv) studying the origins and functions of inflammatory cells observed in these mouse tumors. To pursue these goals, we will take advantage of several conditional mouse mutants, results from our own proteomics surveys, the Sleeping Beauty transposition system, and methods for characterization of immune cells. We expect our findings to offer new insights into EGFR-mediated lung carcinogenesis, tumor progression, secondary drug resistance, and the role of immune cells in solid tumors. In addition, we may generate new mouse tumor cell lines for experimental use and identify genes that are useful for diagnosis, classification, and treatment of lung cancers.